CN104644578A - Sitagliptin phosphate composition tablet and preparation method thereof - Google Patents
Sitagliptin phosphate composition tablet and preparation method thereof Download PDFInfo
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- CN104644578A CN104644578A CN201310600545.1A CN201310600545A CN104644578A CN 104644578 A CN104644578 A CN 104644578A CN 201310600545 A CN201310600545 A CN 201310600545A CN 104644578 A CN104644578 A CN 104644578A
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Abstract
The invention relates to the field of pharmacy, and discloses a sitagliptin phosphate composition tablet and a preparation method thereof. The sitagliptin phosphate composition tablet disclosed by the invention comprises the following effective components: sitagliptin phosphate, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate and 5% hydroxy propyl cellulose. The sitagliptin phosphate composition tablet is available in synthesis materials, low in cost, high in disintegrating speed, high in dissolution rate, good in stability, accurate in dosage, convenient to take and convenient to carry. The method for preparing the sitagliptin phosphate composition tablet is simple in steps, short in production cycle, low in production cost and suitable for industrialized application; and the technological process is easy to control.
Description
Technical field
The present invention relates to medical domain, disclose a kind of phosphoric acid sitagliptin composition tablet and preparation method thereof.
Background technology
Diabetes act on body by the various virulence factor of inherited genetic factors, immunologic function disorder, infected by microbes and toxin thereof, free radical toxin, Nervous and Mental Factors etc. to cause hypoinsulinism and a series of metabolism disorder syndrome such as sugar, protein, fat, water and eletrolytes caused, be main feature clinically with hyperglycemia, the performance such as polyuria, polydipsia, polyphagia can appear in model case, become thin, i.e. " three-many-one-little " symptom.Wherein type 1 diabetes is multiple is born in teenager, because insulin secretion lacks, must rely on exogenous insulin and supplement to sustain life.Wherein type 1 diabetes is multiple is born in teenager, because insulin secretion lacks, must rely on exogenous insulin and supplement to sustain life; During type 2 diabetes mellitus is more common in, old people, the secretory volume of its insulin is not low, even also higher, and clinical manifestation is that body is responsive not to insulin, i.e. insulin resistant.Diabetes can cause infection, heart change, cerebrovascular disease, renal failure, lose the sight of both eyes, lower limb gangrene etc. and become the lethal main cause disabled.Diabetes are high oozes the serious acute complication that syndrome is diabetes, starting stage can show as polyuria, polydipsia, fatigue and weakness, bradykinesia etc., along with the increase state of an illness of body fluid loss sharply develops, occur that drowsiness, disorientation, epileptic are twitched, the symptom of the similar apoplexy such as hemiplegia, even goes into a coma.
DPP IV (DPP-IV) is the novel targets for the treatment of type 2 diabetes mellitus, and it can the multiple hormone such as rapid inactivation incretin glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP).DPP-IV inhibitor then extends and improves the activity of endogenous GLP-1 and GIP, promotes insulin secretion, reduces blood glucose.Current DPP-IV inhibitor is mainly divided into 2 classes, the DPP-IV inhibitor that namely substrate is similar and the similar DPP-IV inhibitor of non-substrate.The DPP-IV inhibitor research and development comparatively morning that substrate is similar, there is the structure similar to DPP-IV natural substrate, be combined with DPP-IV competitively, but do not activate its downstream reaction, abiology effect.Again according to the serine residue of DPP-IV whether with electrophilic group covalent bond; be divided into covalency and non-covalent 2 subclass: the former is as vildagliptin and BMS-477118; the latter as glutamyl Thiazolidine, LC-150133, the latter due to untoward reaction obvious, substantially stop research and development.The similar DPP-IV inhibitor of non-substrate, by being combined with one or more functional groups of DPP-IV, blocks its downstream biological effect, thus plays inhibitory action.Have 4 subclass such as the amino phenylpropyl alcohol quinolizine derivatives of amphetamine, xanthine, hybar X analog derivative and 2-at present, representative drugs has sitagliptin and Egelieting.
Phosphoric acid sitagliptin is developed by MSD Corp., is the DPP-IV inhibitor class medicine of first acquisition FDA (Food and Drug Adminstration) approval listing, in listing in 2006, and trade name: Jie Nuowei
?, approval listing specification is 100mg.Phosphoric acid sitagliptin is used for the treatment of type 2 diabetes mellitus.
Phosphoric acid sitagliptin, molecular formula: C
16h
18f
6n
5o
5p, structural formula is as follows:
Produced by MSD Corp. the earliest, but have that disintegration rate is slow, dissolution rate is low and the shortcoming of inconvenient use.
Summary of the invention
The first object of the present invention is to provide a kind of phosphoric acid sitagliptin composition tablet, the effective ingredient of described phosphoric acid sitagliptin composition tablet is phosphoric acid sitagliptin, mannitol, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, magnesium stearate and 5% hydroxypropyl cellulose aqueous solution, have that synthesis material is easy to get, cost is low, and disintegration rate is fast, dissolution rate is high, good stability, dosage accurately, taking convenience, the feature such as be easy to carry.
In order to reach above technique effect, technical scheme of the present invention is as follows:
Produce the phosphoric acid sitagliptin composition tablet of 100mg specification, with weight parts, the effective ingredient of described phosphoric acid sitagliptin composition tablet is phosphoric acid sitagliptin 100 parts, 130 parts, mannitol, microcrystalline Cellulose 130 parts, cross-linking sodium carboxymethyl cellulose 8 parts, magnesium stearate 16 parts and 5% hydroxypropyl cellulose aqueous solution 15 parts.
Phosphoric acid sitagliptin composition tablet of the present invention with phosphoric acid sitagliptin for active constituents of medicine, be equipped with certain mannitol, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, magnesium stearate and 5% hydroxypropyl cellulose aqueous solution make.
Because phosphoric acid sitagliptin itself is poorly soluble, for increasing disintegration time and the dissolution of tablet, add cross-linking sodium carboxymethyl cellulose as disintegrating agent, add hydroxypropyl cellulose aqueous solution as binding agent, add mannitol and microcrystalline Cellulose as filler, add magnesium stearate as lubricant.
Cross-linking sodium carboxymethyl cellulose is the ether of water-soluble cellulose, and the carboxyl about having 70% is sodium-salt type, have larger draw moist, due to the existence of cross-bond, water insoluble, can absorb in water several times amount water expand and insoluble, there is good disintegration and compressibility.
Hydroxypropyl cellulose is water-soluble and multiple organic solvent at normal temperatures, as: absolute methanol, ethanol, isopropyl alcohol, propylene glycol, dichloromethane, also acetone, chloroform, toluene and cellosolve is dissolved in, solution is all transparent, be good thermoplastic, have excellent film property, institute's film forming is very tough and tensile, glossiness is good, and elasticity is abundant; Ash is extremely low, makes this product have excellent caking property, as emulsion thickening use, very stable, and good dispersion.
Mannitol (Mannitol), also known as D-mannital, is the hexahydroxylic alcohols that a kind of people are familiar with, and is isomers with sorbitol.It is a kind of non-hygroscopic, odorless, white or colourless crystalline powder.Mannitol has pleasant sweet taste, and its sugariness is 0.55-0.65 times of sucrose, has the general character of multi-sugar alcohol.Mannitol is a kind of functional Sugar Alcohol entering people's life the earliest.In functional Sugar Alcohol, mannitol is the hexabasic alcohol of uniquely a kind of not easily moisture absorption, has the features such as sugariness is suitable, heat is low, have no side effect simultaneously.In human physiological metabolism, it is the same with other functional sugar alcohol, has and has nothing to do with insulin, do not improve blood glucose value, the features such as unlikely dental caries, can be used as the sweeting agent of diabetes patient, adiposis patient.
Microcrystalline Cellulose is a kind of tasteless, imperceptible white corynebacterium cellular granule, and it does not have fibroid and mobility is extremely strong, in carboxymethyl acidylate, acetylation, esterification process, have higher reactivity worth, very favourable to chemical modification.Owing to there is hydrogen bond between microcrystalline Cellulose molecule, hydrogen bond association during pressurized, admittedly the compressibility with height, meanwhile, after the tablet of compacting runs into liquid, the tablet that moisture enters rapidly containing microcrystalline Cellulose is inner, and hydrogen bond ruptures at once.Microcrystalline Cellulose in Dimemorfan phosphate tablet composite of the present invention, substantially increases the hardness of tablet, disintegrative and compressibility.
Magnesium stearate is hydrophobic lubricant, and its quality is very soft, is therefore mainly used as lubricant; play and fill and lead up particle surface and cheat recessed effect, use the packing interaction between rear granule to die down, be easy to each other slide; easy and granule mixes, and after tabletting, unilateral smooth and beautiful appearance, most widely used.
The invention also discloses a kind of preparation method of phosphoric acid sitagliptin composition tablet, comprise the following steps:
(1) sieve: phosphoric acid sitagliptin is crossed 90-110 mesh sieve, sieve mannitol, microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose 70-95 mesh sieve respectively;
(2) mix: the phosphoric acid sitagliptin weighed up according to quantity, mannitol, microcrystalline Cellulose and the cross-linking sodium carboxymethyl cellulose mix homogeneously after sieving is obtained the first mixture for subsequent use;
(3) granulate: the hydroxypropyl cellulose aqueous solution of weigh up 5% is added soft material processed in the first mixture, granulate after crossing 20-25 mesh sieve;
(4) granule of step (3) is dried to moisture at 60 DEG C and is not more than 3.5%, excessively granulate after 15-25 mesh sieve, then add the magnesium stearate mix homogeneously weighed up, after measuring intermediates content, namely tabletting obtains phosphoric acid sitagliptin tablet composition.
Preferably, the phosphoric acid sitagliptin described in step (1) crosses 100 mesh sieves, and described mannitol, microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose cross 80 mesh sieves respectively.
Preferably, sieving as crossing 24 mesh sieves in step (3).Preferably, sieving as crossing 20 mesh sieves in step (4).
Preferably, the tableting processes tablet hardness in step (4) controls to be not less than 8Kg/mm
2.
The effect adopting above-mentioned preparation method to have is: step is simple, and technical process easily controls, with short production cycle, and production cost is low, is applicable to industrial applications.
Apply technical scheme of the present invention, there is following technique effect: the effective ingredient of (1) phosphoric acid sitagliptin of the present invention composition tablet is phosphoric acid sitagliptin, mannitol, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, magnesium stearate and 5% hydroxypropyl cellulose aqueous solution, have that synthesis material is easy to get, cost is low, and disintegration rate is fast, dissolution rate is high, good stability, dosage accurately, taking convenience, the feature such as be easy to carry; (2) the present invention prepares the method step of phosphoric acid sitagliptin composition tablet simply, and technical process easily controls, with short production cycle, and production cost is low, is applicable to industrial applications.
Detailed description of the invention
Describe technical scheme of the present invention in detail below in conjunction with specific embodiments, be used for explaining technical scheme of the present invention in this illustrative examples of the present invention and explanation, but not as a limitation of the invention.
Embodiment 1:
Produce the phosphoric acid sitagliptin composition tablet that 1000 specifications are 100mg, the effective ingredient of described phosphoric acid sitagliptin composition tablet is phosphoric acid sitagliptin, mannitol, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, magnesium stearate and 5% hydroxypropyl cellulose aqueous solution, and the consumption of each raw material is as shown in table 1.
concrete preparation process is as follows:
The first step: sieve, crosses 100 mesh sieves by phosphoric acid sitagliptin, and mannitol, microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose are crossed 80 mesh sieves respectively;
Second step: mixing, obtains the first mixture by the phosphoric acid sitagliptin weighed up according to quantity, mannitol, microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose mix homogeneously after sieving, for subsequent use;
3rd step: granulate, the hydroxypropyl cellulose aqueous solution of weigh up 5% is added soft material processed in the first mixture, granulates after crossing 24 mesh sieves;
4th step: the granule of step (3) is dried to moisture at 60 DEG C and is not more than 3.5%, cross 20 mesh sieve granulate, add the magnesium stearate mix homogeneously weighed up again, namely tabletting obtains phosphoric acid sitagliptin tablet composition, and shown tableting processes tablet hardness controls to be not less than 8Kg/mm
2.
The indices of the phosphoric acid sitagliptin composition tablet obtained according to this formula and this method is as shown in table 2:
The indices tables of data of table 2 phosphoric acid sitagliptin composition tablet
Phosphoric acid sitagliptin composition tablet synthesis material is easy to get, cost is low, and disintegration rate is fast, dissolution rate is high, good stability, dosage accurately, taking convenience, to be easy to carry; Above-mentioned preparation method step is simple, technical process easily controls, with short production cycle, production cost is low, be applicable to industrial applications.
Embodiment 2:
Adopt the formula of embodiment 1 to carry out scale-up, the concrete consumption of raw material is as follows:
Table 3 specification is the phosphoric acid sitagliptin composition tablet scale-up raw material dosage of 100mg
In concrete technology, controling parameters is as shown in table 4:
The control table of table 4 key process parameter
Result shows, in amplification process, and the equal practical of formulation and technology of this specification preparation, process stabilizing.Carry out index investigation to the sample of preparation with reference to embodiment 2, indices all meets clinical research quality standard.
The detecting instrument used in above embodiment 1, embodiment 2 technique and detection method thereof are summed up as follows:
1, pellet moisture: adopt Ka Shi micro-water analyzer, measures pellet moisture with reference to " Chinese Pharmacopoeia " version in 2010 two annex VIII M first method A.
2, tablet friability inspection: adopt tablet friability analyzer, checks with reference to " Chinese Pharmacopoeia " version in 2010 two annex XG.
3, check tablet hardness and disintegration: adopt tablet four-function analyzer, check with reference to " Chinese Pharmacopoeia " version in 2010 two annex XA.
4, dissolution test: with reference to " Chinese Pharmacopoeia " version (two) dissolution method (annex Ⅹ C second method) in 2010, specific as follows:
With water 900ml for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, through 30 minutes, get solution to filter in right amount, get subsequent filtrate (sample concentration 12.5 μ g/ml) as need testing solution, it is appropriate that another precision takes phosphoric acid sitagliptin reference substance, is diluted to the sitagliptin in contrast product solution of every 1ml about containing 12.5 μ g with dissolution medium; Get above-mentioned two kinds of solution respectively and measure trap in 275nm wavelength place, calculate the stripping quantity of every sheet.
5, Related substances separation: with reference to phosphoric acid sitagliptin raw material detection method, measure according to high performance liquid chromatography (" Chinese Pharmacopoeia " version in 2010 two annex V D).
(1) chromatographic condition: determined wavelength is 224nm, column temperature is 30 DEG C, and flow velocity is 1.0ml/min, and number of theoretical plate is not less than 3000 by phosphoric acid sitagliptin.
(2) mobile phase A is 0.1% high chloro acid solution (containing 0.3% triethylamine) (pH=3.0), and Mobile phase B is acetonitrile, shown in table 5 specific as follows:
The mapping table of table 5 mobile phase A and Mobile phase B and time
(3) system suitability: get each about 5mg of phosphoric acid sitagliptin and impurity F 1008 and put in 10ml and 1000ml measuring bottle respectively, add the initial flow mutual-assistance dissolve and be diluted to scale, shake up, get above-mentioned two kinds of solution 2ml respectively to mix, precision measures mixed solution 20 μ L and enters chromatograph of liquid, record chromatogram (peak sequence is followed successively by sitagliptin and impurity F 1008), number of theoretical plate calculates by sitagliptin peak and is not less than 3000.
(4) algoscopy: get this product, porphyrize, precision takes fine powder appropriate (being about equivalent to phosphoric acid sitagliptin 10mg) and puts in 20ml volumetric flask, adds initial flow phased soln and dilute to put scale, filters, and makes every 1ml about containing the solution of 0.5mg, as need testing solution; Precision measures need testing solution 20 μ L, respectively injection liquid chromatography, and record chromatogram is to 5 times of main constituent peak retention time.After deduction solvent peak, if any impurity peaks in need testing solution chromatogram, detect single maximum contaminant and total impurities content.
(5) assay: with reference to phosphoric acid sitagliptin raw material detection method, measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).
Chromatographic condition is as follows with reference to the chromatographic condition of Related substances separation:
Chromatographic column: YMCC18 post;
Mobile phase: acetonitrile-0.1% perchloric acid (containing 0.3% triethylamine) (pH=3.0)=20:80;
Survey wavelength: 224nm;
Column temperature: 30 DEG C;
Sample size: 20 μ L;
Method: get this product, porphyrize, precision takes fine powder appropriate (being about equivalent to phosphoric acid sitagliptin 12.5mg), puts in 25ml volumetric flask, adds mobile phase and dissolves and dilute and put scale, shake up filtration; Precision measures 1ml and puts in 10ml volumetric flask, adds mobile phase and is diluted to scale, shake up, obtain need testing solution.It is appropriate that another precision takes reference substance, is made in the same way of every 1ml about containing 50 μ g phosphoric acid sitagliptin solution, product solution in contrast.Precision measures need testing solution and reference substance solution 20 μ L injection liquid chromatography, and record chromatogram, by external standard method with calculated by peak area this product content.
The above is the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications are also considered as protection scope of the present invention.
Claims (6)
1. a phosphoric acid sitagliptin composition tablet, it is characterized in that: with weight parts, the effective ingredient of described phosphoric acid sitagliptin composition tablet is phosphoric acid sitagliptin 100 parts, 130 parts, mannitol, microcrystalline Cellulose 130 parts, cross-linking sodium carboxymethyl cellulose 8 parts, magnesium stearate 16 parts and 5% hydroxypropyl cellulose aqueous solution 15 parts.
2. a preparation method for the phosphoric acid sitagliptin composition tablet as described in claim 1, is characterized in that: with weight parts, comprises the following steps:
(1) sieve: phosphoric acid sitagliptin is crossed 90-110 mesh sieve, sieve mannitol, microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose 70-95 mesh sieve respectively;
(2) mix: take the phosphoric acid sitagliptin of 100 parts after step (1) is sieved, the mannitol of 130 parts, 130 parts of microcrystalline Cellulose and 8 parts connection sodium carboxymethyl cellulose mix homogeneously obtain the first mixture, for subsequent use;
(3) granulate: 5% hydroxypropyl cellulose aqueous solution of 15 parts is added soft material processed in described first mixture, granulate after crossing 20-25 mesh sieve;
(4) granule of step (3) is dried to moisture at 60 DEG C and is not more than 3.5%, excessively granulate after 15-25 mesh sieve, then add the magnesium stearate mix homogeneously of 16 parts, after measuring intermediates content, namely tabletting obtains phosphoric acid sitagliptin tablet composition.
3. the preparation method of phosphoric acid sitagliptin composition tablet according to claim 2, it is characterized in that: the phosphoric acid sitagliptin described in step (1) crosses 100 mesh sieves, described mannitol, microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose cross 80 mesh sieves respectively.
4. the preparation method of phosphoric acid sitagliptin composition tablet according to claim 2, is characterized in that: sieving as crossing 24 mesh sieves in step (3).
5. the preparation method of phosphoric acid sitagliptin composition tablet according to claim 2, is characterized in that: sieving as crossing 20 mesh sieves in step (4).
6. the preparation method of phosphoric acid sitagliptin composition tablet according to claim 2, is characterized in that: in step (4), in tableting processes, tablet hardness controls to be not less than 8Kg/mm
2.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104771377A (en) * | 2015-04-15 | 2015-07-15 | 海南华益泰康药业有限公司 | Preparation method of immediate release oral preparation containing sitagliptin or sitagliptin pharmaceutical salt |
| CN106568849A (en) * | 2015-10-10 | 2017-04-19 | 深圳翰宇药业股份有限公司 | Detection method for related substances in saxagliptin |
| CN106822017A (en) * | 2016-12-31 | 2017-06-13 | 辰欣药业股份有限公司 | A kind of phosphoric acid Xi Gelieting pieces and preparation method thereof |
| CN106880618A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of phosphoric acid Xi Gelieting capsules and preparation method thereof |
| CN113750060A (en) * | 2021-08-03 | 2021-12-07 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of sitagliptin phosphate tablets |
| CN116082346A (en) * | 2023-04-12 | 2023-05-09 | 宙晟智维生命科学(上海)有限公司 | High-fluidity sitagliptin phosphate monohydrate crystal and preparation method thereof |
-
2013
- 2013-11-25 CN CN201310600545.1A patent/CN104644578A/en not_active Withdrawn
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104771377A (en) * | 2015-04-15 | 2015-07-15 | 海南华益泰康药业有限公司 | Preparation method of immediate release oral preparation containing sitagliptin or sitagliptin pharmaceutical salt |
| CN104771377B (en) * | 2015-04-15 | 2017-06-09 | 海南华益泰康药业有限公司 | A kind of preparation method of the oral preparation of quick releasing containing sitagliptin or its pharmaceutical salts |
| CN106568849A (en) * | 2015-10-10 | 2017-04-19 | 深圳翰宇药业股份有限公司 | Detection method for related substances in saxagliptin |
| CN106880618A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of phosphoric acid Xi Gelieting capsules and preparation method thereof |
| CN106822017A (en) * | 2016-12-31 | 2017-06-13 | 辰欣药业股份有限公司 | A kind of phosphoric acid Xi Gelieting pieces and preparation method thereof |
| CN113750060A (en) * | 2021-08-03 | 2021-12-07 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of sitagliptin phosphate tablets |
| CN116082346A (en) * | 2023-04-12 | 2023-05-09 | 宙晟智维生命科学(上海)有限公司 | High-fluidity sitagliptin phosphate monohydrate crystal and preparation method thereof |
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Application publication date: 20150527 |